Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Reprod Toxicol. 2018 Aug;79:47-56. doi: 10.1016/j.reprotox.2018.05.005. Epub 2018 May 22.
Epidemiological surveys suggest that adult hypercholesterolemia has an intrauterine origin and exhibits gender differences. Our previous study demonstrated that adult rats with intrauterine growth retardation (IUGR) offspring rats induced by prenatal caffeine exposure (PCE) had a higher serum total cholesterol (TCH) level. In this study, we aimed to analyze the influencing factors, underlying mechanism and interactions affecting hypercholesterolemia in adult offspring with caffeine exposure during pregnancy. Pregnant rats were administered caffeine (120 mg/kg d) from gestational day 11 until delivery. Offspring rats fed a normal diet or a high-fat diet (HFD) were euthanized at postnatal week 24, and blood and liver samples were collected. The results showed that PCE could increase the serum levels of TCH and low-density lipoprotein-cholesterol (LDL-C), and the hepatic expression of HMG CoA reductase (HMGCR) and apolipoprotein B (ApoB), but decreased the high-density lipoprotein-cholesterol (HDL-C) level and the hepatic expression of scavenger receptor B1 (SR-B1) and LDL receptor (LDLR). Furthermore, PCE, HFD and gender interact with each other to influence the serum cholesterol phenotype and expression of hepatic cholesterol metabolic genes. These results suggest that the hypercholesterolemia in adult offspring rats induced by PCE mainly resulted from enhanced synthesis and the weakened reverse transport of cholesterol in the liver, furthermore HFD could aggravate this effect, which is caused by hepatic cholesterol metabolic disorders. Moreover, cholesterol metabolism in female rats was more sensitive to neuroendocrine changes and HFD than that in males. This study confirmed the influencing factors (such as a HFD and female gender) of hypercholesterolemia in IUGR offspring providing theoretical and experimental bases for the effective prevention of fetal-originated hypercholesterolemia.
流行病学调查表明，成人高胆固醇血症具有宫内起源，并表现出性别差异。我们之前的研究表明，产前咖啡因暴露（PCE）诱导的宫内发育迟缓（IUGR）大鼠的成年后代大鼠血清总胆固醇（TCH）水平较高。在这项研究中，我们旨在分析影响因素、潜在机制以及在怀孕期间暴露于咖啡因对成年后代高胆固醇血症的相互作用。从妊娠第 11 天到分娩，给怀孕的大鼠给予咖啡因（120mg/kg/d）。后代大鼠在产后第 24 周喂食正常饮食或高脂肪饮食（HFD），然后处死，并采集血液和肝脏样本。结果表明，PCE 可增加血清 TCH 和低密度脂蛋白胆固醇（LDL-C）水平，以及肝脏中 HMG CoA 还原酶（HMGCR）和载脂蛋白 B（ApoB）的表达，但降低了高密度脂蛋白胆固醇（HDL-C）水平和肝脏中清道夫受体 B1（SR-B1）和 LDL 受体（LDLR）的表达。此外，PCE、HFD 和性别相互作用，共同影响血清胆固醇表型和肝脏胆固醇代谢基因的表达。这些结果表明，PCE 诱导的成年大鼠后代高胆固醇血症主要是由于肝脏中胆固醇合成增强和逆向转运减弱所致，此外，HFD 可加重这种作用，导致肝脏胆固醇代谢紊乱。此外，雌性大鼠的胆固醇代谢对神经内分泌变化和 HFD 的敏感性高于雄性大鼠。本研究证实了高胆固醇血症的影响因素（如 HFD 和女性性别），为有效预防胎儿起源的高胆固醇血症提供了理论和实验依据。
